1. Field of the Invention
This invention relates to prostacyclin (PGI.sub.2) analogues which are used as antithromboic and antiulcer drugs in the field of medicines. In more detail, this invention relates to the compounds represented by the general formula (I) or their salts, which have prostacyclin (PGI.sub.2)-like inhibitory activity against platelet agglutination and antiulcer activity.
2. General Formula ##STR2## where R.sub.1 is hydrogen or lower alkyl; R.sub.2 is lower alkyl, lower alkenyl, lower alkynyl, lower aralkynyl, lower alkyloxy, arylthio, or cyano; R.sub.3 and R.sub.4 each is hydrogen or hydroxy-protecting group; R.sub.5 is straight or branched alkyl which may be substituted with heterocycle, straight or branched alkynyl, or cycloalkyl; the wavy line indicates R- or S-configuration, or their mixture:
PGI.sub.2 is produced mainly in the vascular cell or leukocytes as follows. Phospholipase A.sub.2 activated by chemical or physical stimulation of the vascular cell, accelerates release of arachidonic acid which is converted into PGI.sub.2 by the action of cyclooxygenase and PGI.sub.2 synthetase, PGI.sub.2 has a potent inhibitory activity against platelet agglutination and vasodilative activity and is used as an antiplatelet agent for patients who have been treated with artificial dialysis or pump-oxygenator. As the other clinical applications of PGI.sub.2, the applications to thrombotic diseases such as peripheral circulatory insufficiency, e.g., vibration disease, collagen diseases, Buerger disease, and arteriosclerosis obliterans; ischemic heart diseases, e.g., angina pectoris and myocardial infarction; and disturbance of cerebral circulation, e.g., cerebral thrombosis, cerebral embolis and cerebral infarction, are expected. However, PGI.sub.2 also has several problems; for example, it is chemically unstable and has hypotensive activity, which is undesirable for antithromboic drugs. Therefore, it has been desired that the chemically stable PGI.sub.2 analogues having more potent platelet agglutination inhibitory activity and higher selectivity of the action are developed.
The present inventors have prepared the prostacyclin analogues represented by the general formula (I), and found that these novel compounds have a potent activity as PGI.sub.2 receptor agonists and are chemically stable. The present invention is based upon these findings.